The long-term goal of this project is to delineate the mechanism by which environmental aldehydes alter cardiac function and modify pathologic cardiac phenotypes. Based on our preliminary studies, we propose that exposure to environmental aldehydes induces oxidative stress that acutely depresses myocardial contractility and exacerbates sensitivity to ischemia. Chronic exposures on the other hand, induce an inflammatory state that contributes to myocardial dysfunction and remodeling characteristic of heart failure. To test this hypothesis we will examine the cardiotoxicity of acrolein and trans-2-hexenal, which are two of the most abundant and toxic aldehydes present in the environment. Our first aim is to delineate the acute effects of these aldehyde on contractile function add left ventricular performance. Using isolated cardiac myocytes we will identify changes in excitation-contraction coupling due to aldehyde exposure and in corresponding in vivo experiments we will examine aldehyde-induced changes in LV function and verticuloarterial (VA) coupling. These experiments are designed to test the possbility that acute contractile depression in response to aldehyde exposure is in part due to reduced calcium responsiveness of myofitaments. In collaboration with Projects II and III, using apoE-null mice, we will define how hypercholesterolemia and existing atherosclerosis affects aldehyde-induced myocardial injury and dysfunction. The second aim of the project is to define the mechanisms by which aldehydes exacerbate ischemic injury. For this, we will test whether aldehyde exposure increases the severity of myocardial infarction and abolishes cardioprotective signaling associated with delayed ischemic preconditioning. To identify the locus of injury, we will examine aldehyde-induced changes in PKC-epsilon-dependent signaling that plays a key role in establishing the cardioprotective phenotype. Our last aim is to test the hypothesis that chronic aldehyde exposures establish myocardial inflammation, which induces myocardial remodeling and heart failure phenotype and exacerbates post-infarct LV remodeling. Chronic myocardial inflammation will be assessed by measuring the activity of the transcription factor NF-kappaB and by increased expression of cytokines. Finally, to identify the role of metabolism as a determinant of aldehyde cardiotoxicity, we will examine whether LV remodeling is exacerbated in GSTA4- and GSTP1-null mice. Collectively, the results of these investigations will provide a critical assessment of the myocardial dsk associated with exposure to environmental aldehydes and establish specific molecular mechanisms whereby toxic aldehydes in the environment induce myocardial dysfunction and exacerbate myocardial disease.